I. Computer-assisted self-infusion of ethanol (CASE) in humans Self-administration is a hallmark of all addictive drugs, including alcohol. Human alcohol self-administration is typically assessed by measuring the oral intake of alcoholic beverages in a laboratory bar setting. These methods are limited by the high PK variability in alcohol exposures, differences in the definition of standardized drinks and drinking schedules, as well as non-pharmacological influences such as expectancy, beverage preference, and choice of incentives for drinking. The CASE method provides subjects with the flexibility to choose when to push a button to receive alcohol, while providing the investigator with flexibility in controlling the consequent BrAC (and thus brain alcohol exposure) by assuring the same increment across all subjects. Thus, the CASE method assesses behavior driven by the pharmacological effects of alcohol. The first phase of this project was to characterize ad-lib IV alcohol self-administration and resulting BrACs and PD responses in non-dependent drinkers. During the session, subjects first underwent a directed priming phase, where they were prompted to push a button to receive standardized alcohol infusions, followed by an ad-lib phase, where they had free access to the same infusions. Primary measures include number of button presses, average and peak BrAC. The ad-lib paradigm was previously shown to be reliable and reproducible, with high test-retest correlations between sessions (r>0.6), and high internal consistency among measures within sessions (r>0.7). Since then, the sample was expanded to 106 non-dependent drinkers, and confirmed preliminary findings of significant associations between self-administration measures and drinking history. Additionally, self-report measures of liking drug effects and urges following priming predicted self-administration measures during the ad lib phase, and there was a strong association between self-administration measures and peak alcohol effects of feeling drug effects, liking drug effects, intoxication and stimulation. The second phase of this project has focused on developing an operant paradigm, using a progressive ratio (PR) schedule that requires subjects to press the button an increasing number of times for each subsequent alcohol exposure. This PR-CASE method assesses motivation for alcohol reward, and is based on the principle that people will work harder for greater rewards. Outcome measures include the total number of rewards and total ethanol earned, as well as the average and peak BrAC achieved. Results from a reliability study (n=11) showed very high test-retest correlations (r>0.8) for measures between sessions. Results from a larger sample (n=57) show significant association between recent drinking history and self-administration measures, with heavier drinkers showing higher BrACs and total ethanol earned. Subjective measures of alcohol effects and urges after priming were significantly associated with alcohol self-administration. Self-administration measures obtained from the PR paradigm were sensitive to expectancy of alcohol effects. Exposure-response analysis supported the role of the rewarding and motivating effects of alcohol driving alcohol self-administration behavior. Study participants that completed the PR-CASE session also participated in an ad-lib self-administration session, which provides a unique opportunity to compare and contrast self-administration measures under these two operant schedules within the same individuals. This ongoing analysis will help improve our understanding of individual differences in the rewarding properties of alcohol that drive self-administration behavior. II. Human Laboratory Models in Medication Development for Alcoholism The Section is invested in developing and utilizing human alcohol self-administration paradigms, using CASE, to examine the effects of pharmacological agents being developed for the treatment of alcoholism. These studies will complement studies using well-established animal models for alcoholism that are used for screening of novel therapeutics to help identify treatments that are likely to succeed in clinical trials, thus facilitating future medication development for alcoholism. The first experimental medicine initiated by the Section is designed to examine the effect of varenicline, a (nicotinic) acetylcholine receptor partial agonist, on alcohol self-administration using the CASE method in non-treatment seeking heavy drinkers. Varenicline, an oral medication approved by the FDA for smoking cessation, has demonstrated effectiveness in reducing alcohol consumption in a rodent model of alcohol dependence and in heavy drinking smokers. This study is a randomized, placebo-controlled study in 21-60 year-old non-treatment-seeking heavy drinkers in good physical and psychiatric health. Subjects underwent a baseline CASE session, after which they were randomized to 3 weeks of treatment with varenicline or placebo. Following approximately 2 weeks of treatment, subjects undergo an fMRI scan to examine the effect of varenicline on brain reward systems underlying incentive motivation for alcohol, as well as neural activation in response to IV alcohol. At the end of 3 weeks of treatment, subjects repeated the CASE session to measure changes in IV self-administration. Data analysis for this study is ongoing. The sample includes 22 subjects (9 smokers) in the placebo group and 24 subjects (11 smokers) in the varenicline group. Subjects were heavy drinkers with an average of 6 drinks per drinking day, and average AUDIT score of 13.5. Preliminary analysis of fMRI data thus far appears to be promising. Subjects were scanned while performing the Alcohol-Food Incentive Delay (AFID) task, a version of the MID task where they can win points for IV alcohol infusions or snack foods. Analysis of BOLD response to the presentation of alcohol cues and notification of alcohol rewards showed significant activation of striatal areas in the placebo group but not in the varenicline group (p<0.01, k>10). Subjects in the varenicline group also reported lower feelings of happiness and excitement (on subjective mood scales) in response to alcohol cues compared to the placebo group. Additional fMRI analyses to examine varenicline-induced signal changes in specific regions of interest associated with reward, as well as functional connectivity analysis to examine the relationships between these striatal activations and changes in other brain regions are ongoing. Analyses of IV self-administration measures are also compared between treatment groups. This study will provide important information on the effect of varenicline on the neural correlates of incentive salience for alcohol, as well as on alcohol self-administration behavior. This study would help further establish the use of human laboratory paradigms in medications development for alcohol use disorders. III. Collaborative Studies: 1) Effect of naltrexone on the BOLD signal in the ventral striatum during the alcohol clamp in alcohol-dependent individuals (David T. George, PI). Data analysis has been completed, and the study manuscript is currently in review. 2) Measuring Effects of Acute Alcohol on Human Brain Metabolites using Magnetic Resonance Spectroscopy (Reza Momenan, PI). This study was initiated in 2011 and is ongoing. 3) Effects of Ghrelin on Alcohol Administration in Non-Treatment Seeking Heavy Drinkers (Lorenzo Leggio, PI). This study was initiated in 2012 and is ongoing.